Drs. Lea Starita and Andrew Stergachis: 'We intend to remove this significant obstacle both researchers and clinicians face in clinical genomics.'
“A major challenge in human genetics is the fact that our ability to read genomes has vastly outpaced our ability to interpret the genetic variants we find.” Dr. Lea Starita, Assistant Professor The Brotman Baty Institute for Precision Medicine (BBI)
A significant endeavor to overcome that challenge will soon be underway.
BBI has been awarded a new five-year, $4.7 million grant from the National Human Genome Research Institute’s Advancing Genomic Medicine Research program to identify the clinical utility of large-scale functional data and how best to translate them so physicians can incorporate that data into their clinical practices.
“We intend to remove this significant obstacle both researchers and clinicians face in clinical genomics,” said BBI’s Dr. Andrew Stergachis, who, along with Starita, is a co-principal investigator on the project. “Many of our patients have what we call a ‘variant of unknown significance’ (VUS), a variation in genetic sequence for which any relevance to disease risk is uncertain. As a result, we are unable to give those patients answers as to whether or not they are at risk for disease.”
Stergachis, a UW assistant professor of Medical Genetics, and Starita will collaborate with other BBI members and an Australia-based researcher on this project, which has three overarching goals:
- Generating a framework for standardizing and disseminating curated large-scale functional data into resources for clinicians, and implementing this framework into the freely accessible NIH-funded ClinVar public archive.
- Performing a proof-of-concept integration of variant level functional data in ClinVar into clinical practice at UW and Fred Hutch for evaluating the clinical uptake and impacts of variant-level functional data.
- Creating and disseminating resources to train clinicians on best practices for integrating functional data into clinical practice internationally.
“I am confident our team’s collective expertise in functional data generation, software development, and clinical practice will achieve these deliverables,” Starita said. “All of us are committed to eliminating VUS and helping clinicians and researchers in the health care, research, and industrial sectors throughout the world have access what they need – high quality, multiplexed functional data.”
Additional BBI faculty on the grant are (left to right): Drs. Marianne Dubard-Gault, Doug Fowler, Abbye McEwen, and Brian Shirts.
That team includes: Dr. Marianne Dubard-Gault, Medical Director of the Cancer Genetics Service at Fred Hutchinson Cancer Center; Dr. Doug Fowler: Associate Professor, Department of Genomic Sciences, University of Washington; Dr. Abbye McEwen, Acting Instructor, Department of Laboratory Medicine and Pathology at the University of Washington; Dr. Alan Rubin Senior Research Officer, Walter and Eliza Hall Institute, Multiplexed Assay Technology Hub, Melbourne, Australia; and Dr. Brian Shirts: Associate Professor of Laboratory Medicine, University of Washington.
Starita and Stergachis note that the clinical burden of VUSs is disproportionately shouldered by individuals from populations historically excluded from medical research, therefore exacerbating discrepancies in genomic medicine. Variant-level functional data, Stergachis said, has the potential to correct this particular healthcare disparity by improving the clinical diagnosis and management of individuals with VUSs.
Moreover, established clinical guidelines recommend using variant functional data for variant interpretation. But roadblocks remain persistent, including the difficulty for clinicians to find, understand, and use this data.
All of the investigators on this grant are quite familiar with genomic variants.
Some of them led the development of multiplexed assays of variant effect (MAVEs), which assess simultaneously the impact of all possible single nucleotide variants in genes of interest, thereby creating comprehensive variant functional data. These data may be used to reinterpret a significant percentage of VUS in clinically important genes, such as BRCA1, PTEN and more.
Stergachis reflected on the potential impact of this work on the next generation of genomic scientists.
“My colleagues and I are truly excited about this project’s potential for improving clinical genomics,” he said. "It’s been rewarding working with this group of clinicians and scientists to help advance our understanding of how to clinically interpret genetic variants and train the next generation of geneticists on this essential step in clinical care. Individuals across different stages of their medical or research training have been engaged in solving this challenge, from genetic counseling students, medical genetics fellows, graduate students to senior faculty.”